1. Field of the Invention
The present invention concerns borderline active dosage forms of beta blockers for short-term therapy of transient functional cardiovascular symptoms.
2. Background of the Invention
It is known that the chemical group of beta receptor blockers are part of the standard long-term therapy of manifest cardiovascular disorders such as hypertension and angina pectoris. The application spectrum of beta blockers also includes the following indications: hyperkinetic heart syndrome, migraines, tremors, glaucoma, anxiety syndromes, and withdrawal syndromes. See H. Lydtin & P. Trenkwalder, New Indications for Therapy with Beta-Receptor Blockers in: Beta-Receptor Blockers, G. Fischer, Stuttgart, 1991, pp. 58ff, incorporated herein by reference.
Cardiovascular disorders can be subdivided diagnostically into those with pathological manifestations (e.g., angina pectoris based an a manifest coronary heart disorder), and into symptomatic types with only transient pathological-manifestations without a pronounced morphologic basis (e.g., situation-related reactive accelerations of the heart rate through exogenous or endogenous physical or psychological stressors). Also classified within this area, in a broader sense, are, for example, transient cardiac ischemias: so-called silent myocardial ischemic episodes which are not noticed by the patient but can be seen in the EKG. Transient manifestations of this type are also referred to as functional or vegetative symptoms and are based primarily on situationally inadequate reactions of the sympathetic nervous system or the adrenergic neurotransmitters released by it.
However, in principle, this diagnostic subdivision comprises therapeutically different objectives and thus imposes different requirements for the beta blocker therapy which basically must take into account the fact that in the vegetative patients it is a matter of largely organically healthy individuals. Consequently, this includes differences in the desired duration of treatment, in the different level of intensity of the therapeutic effect, and different dosing requirements as well as a different evaluation of the associated therapeutic risk-benefit ratio.
Currently available dosage forms of, as well as dosage schemes with, beta blockers in no way take these therapeutically different requirements into account. Thus, identical dosage forms are used without differentiation for the therapy of transient vegetative symptoms even though they were designed for long-term therapy of manifest cardiovascular disorders. There is merely an attempt to adapt, somewhat superficially (e.g., through recommendations to use the minimum doses in the range), within the framework of the dosage spectrum already available for the manifest and chronic syndromes. Nonetheless, this is still done using the same dosing frequencies.
In symptomatic patients with transient cardiovascular reactions, use of the dosage forms of beta blockers as occurs in the therapy of chronic cardiovascular patients is fundamentally a pharmacodynamically unnecessary overdose, with an increased risk of adverse effects.
The entire spectrum of currently available dosage forms of beta blockers desired for long-term therapy reduces, among other things, the overall physical performance capability and affects, for example, lipid and glucose metabolism. See M. Wickelmayr at al., Glucose Metabolism and .beta.-Blockers, Diuretics and Calcium-Antagonists, pp. 29-33, in: Effects of Antihypertensive Treatment on Glucose Metabolism, International Symposium Bu/ hlerhohe 1988, Thieme, Stuttgart--New York 1990, incorporated herein by reference. Since, pharmacokinetically, these dosage forms already cause complete saturation of adrenergic receptors from the outset, the first dose usually already leads, through competitive displacement of endogenous catecholamine, to a long-lasting change of the resting parameters of the cardiovascular system. This is not merely unnecessary for transient vegetative symptoms, but is in fact harmful.
As a consequence, with administration of these customary dosage forms, patients with transient symptoms must also again be gradually withdrawn from this type of beta blocker therapy in order not to be subject to the risk of cardiovascular withdrawal phenomena--so-called rebounds, such as reactive increases in heart rate. Consequently, this imposes a longer than necessary use of beta blockers for these transient symptoms.
All acutely excessive reactions of the sympathetic nervous system to physical and psychological stressors as well as all vegetative individual symptoms which are embedded in various syndromes are vegetative syndromes. For example, even sleep disturbances can be included among the latter. These seriously stressful vegetative symptoms have, however, not been amenable to beta blocker therapy, because of the inappropriate dosage forms and are consequently treated with other therapies. Thus, the primary therapy of sleep disturbances currently uses drugs which act an the central nervous system, primarily drugs from the chemical group of benzodiazepines, as well as derivatives of barbituric acid. Such treatments present quite significant disadvantages. The sedative effects are not only pronounced but also clearly extend, as residual effects, into the daytime phases of physical activities. These include excessive daytime sleepiness and reduction of functional reactivity and attentiveness. These substances also have a significant addiction potential. Withdrawal after repeated administration frequently triggers adverse effects and vegetative disorders are even intensified, which the patients then wish to prevent with further continuation of this therapy.
There is as yet no use of beta blockers for primary therapy of sleep disturbances. This is also not unexpected since with the dosage forms of beta blockers currently in use, sleep disturbances and nightmares actually are among the adverse effects of these therapies. These undesirable side effects must however be attributed, among other things, to the excessively persistent cardiovascular effects of the customary dosage forms of beta blockers. In particular, the lipophilic beta blockers, which penetrate the CNS barriers more readily, lead to particularly pronounced sleep disturbances. See A. Wasterland, Central Nervous System Side Effects with Hydrophilic and Lipophilic Beta Blockers, Eur. J. Clin. Pharmacol. (1985) 23 (Suppl.) 73-76, incorporated herein by reference.
Such adverse side effects also cannot be improved with customary time-released forms of beta blockers, which, for example, are intended to enable a single daily administration. Instead, side-effects are further worsened with such time-released forms since, for pharmacokinetic reasons, these must be dosed even higher to achieve a prolonged persistence of the cardiovascular effects. Extensions of the effects on the vegetative parameters more sensitive to beta blockers, in particular on cardiac chronotropy, are however unnecessary for vegetative symptoms. Thus, the pharmacokinetic half life of the beta blockers, analytically determined only from the plasma concentration, is far shorter than its pharmacodynamic active period. The demonstrable reductions in the heart rate persist well beyond the pharmacokinetic parameters without any therapeutic consequence having been derived for the vegetative parameters.
Scattered reports in the literature point to the fact that in addition to the central nervous causes, peripheral factors may also be implicated in sleep disturbances. Thus, various sleep disturbances clearly coincide with transient vegetative reactions. In poor sleepers, it is possible to detect, in addition to elevated body temperature caused by the central nervous system, elevated secretion of the catecholamines epinephrine and norepinephrine. See K. Adam, in: IHindmarch, H. Ott, Th. Roth (Eds.), Sleep, Benzodiazepines and Performance, Springer, Berlin, 1984, 44-53, incorporated herein by reference. Comparable processes also seem to be present within the framework of female menopause. Thus, significantly increased sleep disturbances occur in this phase characterized by numerous vegetative functional disorders, in particular appearing within the framework of characteristic hot flashes. See D. Sturdee & M. Brincat in: J. Studd, M. Whitehead (Eds.), The Menopause, Blackwell, Oxford, 1988, pp. 24-42, incorporated herein by reference.
Adrenergically induced cardiac manifestations such as tachycardia appear to intensify anxiety attacks. The occurrence of transient anxiety symptoms after experimental adrenergic stimulation in healthy subjects, for example, with intravenous isoprenaline, is known in human pharmacology.
Consequently, from the aforementioned aspects, a reduction of excessive adrenergic stimulation temporarily affecting the heart seems possible as a principle not applied to date in sleep disturbances. The point of action here is the blockade of sleep-disrupting stress factors caused by the central nervous system. This occurs in particular through the chronotropic adrenergic cardiac receptors especially sensitive to beta blockers. The reactive increase in heart rate triggered by the central nervous system is thus prevented and, at the same time, a negative reinforcement on the central nervous system is averted by blockade of the cardiac feedback reaction. Consequently, this leads to the interruption of a circuit developing between the central nervous system and the heart.
However, for a suitable therapy of transient vegetative symptoms with beta blockers, only reductions of nonphysiological adrenergic simulation effects are reasonable with the functional disturbances. In contrast, after these temporary situations subside, persistent long-term effects of the beta blockers on the cardiovascular system, in particular persistent effects on physiological base values of the cardiovascular system, are unnecessary and undesirable. They merely manifest themselves in the reduction of performance and negatively affect the quality of life. Consequently, from a pharmacological standpoint, only a standby situation is required, whereby the pharmacodynamic effect of the beta blocker dosage form is expressed only under stimulation conditions.
Within the framework of various clinical studies with a transdermal system with the beta blocker mepindolol in angina pectoris patients, it was possible to detect serum concentrations of the beta blocker which were lower by a factor of 5 than is the case with the customary therapeutic doses with customary oral application with this beta blocker. With this extraordinarily low concentration of active ingredient, there were differentiated effects on the heart rate. It turned out, as was objectively demonstrated with continuous 24-hour EKGs, that the maximum increases of the heart rate dropped significantly, but the minimum resting rates remained unchanged. This was also accompanied by a significant reduction in silent myocardial ischemic episodes of these patients, thus an improvement in their continuous cardiac circulation. These effects were also successfully reproduced for even shorter applications, e.g., 12-hour applications. See J. Bonelli, P. Gaza, P. Kirsch, R. K. Liedtke, Int. J. Clin. Pharmacal. Therap. Toxicol. 29, 425-430 (1991), incorporated herein by reference.
Thus, the possibility exists to counter functional and transient stimulation phases of the adrenergic system even for a short time without at the same time affecting the basal vegetative homeostasis of the cardiovascular system. In contrast to this, with the use of all dosage forms of beta blockers currently in therapeutic use, even with test subjects with healthy circulation, there are always persistent and significant drops in the physiological resting values of the cardiovascular system, which is associated with a general reduction of physical performance capability.